Type 1 diabetes (T1D) affects 1.4 million people in the U.S. and its incidence has doubled over the past 20 years. The Diabetes Autoimmunity in the Young Study (DAISY) has already provided new clues concerning the etiology and natural history of T1D in early childhood. We hypothesize that the development of T1D reflects two processes, activation of autoimmunity and then relapsing-remitting islet destruction. With the increasing age of the cohort, we are proposing in this application to address unanswered research challenges: 1) To continue the follow-up of the existing cohort until the age of 18 yrs to determine the natural history of islet autoimmunity (IA) and other autoimmune phenotypes and to explore the heterogeneity of IA and T1D in children and adolescents. We will follow for 5 more years already established cohorts of general population children with high risk HLA-DR,DQ genotypes (n=1422) and non-diabetic first degree relatives of patients with T1D (n=1,120), current median age 12.8 yr. We will estimate overall burden of pre-clinical and clinical T1D, celiac, thyroid, adrenal, rheumatic and parietal autoimmune disease in the general population of Colorado by age 18. This will inform future screening and prevention programs. We will further explore the apparent heterogeneity of IA and T1D and its implications for adult-onset diabetes. 2) To evaluate selected environmental risk factors as potential initiators of IA and/or promoters of progression to T1D. The proposed additional follow-up will extend the scope of this study to T1D cases expected between ages 12-18 yr - the peak incidence of T1D. We will continue to evaluate candidate risk factors that appear to operate only as triggers of IA, but also focus on factors that become more important with age and may be the key promoters of progression from IA to T1D. Alternatively, we will seek the factors that slow down the progression and may help IA to remit. 3) To define the effects of early diagnosis and treatment on preservation of endogenous insulin, glycemic control and variability, and quality of life in children with screening-identified T1D. Screening-detected patients avoid ketoacidosis at diagnosis and have higher fasting C-peptide levels, lower HbA1c, and lower insulin dose during the initial year post-diagnosis than community controls. However, no longer-term follow-up data exist to rule out a lead-time bias and confirm the benefit of screening. The proposed studies are important to reach our overarching goals: to find the environmental causes of T1D, develop primary prevention, and inform public health screening for several autoimmune disorders in children and adolescents. We will continue to make every effort to share DAISY resources with multiple investigators studying T1D and other autoimmune diseases, striving for an open-source database and repository.